Adverse Reactions in Clinical Trails

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

The data described below reflect exposure to AVASTIN in 1529 patients, including 665 receiving AVASTIN for at least 6 months and 199 receiving AVASTIN for at least one year. AVASTIN was studied primarily in placebo- and active‑controlled trials (n = 501, and n = 1028, respectively).

Gastrointestinal Perforation

The incidence of gastrointestinal perforation across all studies ranged from 0–3.7%. The incidence of gastrointestinal perforation, in some cases fatal, in patients with mCRC receiving AVASTIN alone or in combination with chemotherapy was 2.4% compared to 0.3% in patients receiving only chemotherapy. The incidence of gastrointestinal perforation in NSCLC patients receiving AVASTIN was 0.9% compared to 0% in patients receiving only chemotherapy. (See WARNINGS: Gastrointestinal Perforations and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Non-Gastrointestinal Fistula Formation

Would Healing Complications

The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving AVASTIN as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus AVASTIN as compared to 4% (1/25) of patients who received bolus‑IFL alone. In the same study, the incidence of wound dehiscence was also higher in the AVASTIN‑treated patients (1% vs. 0.5%).

Venous Thromboembolic Events

The incidence of NCI‑CTC grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving AVASTIN with chemotherapy as compared to those receiving chemotherapy alone. In addition, in patients with mCRC, the risk of developing a second subsequent thromboembolic event in patients receiving AVASTIN and chemotherapy is increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus AVASTIN arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus AVASTIN and 3% (1/30) of patients receiving bolus‑IFL alone.

1 This includes patients with either a systolic or diastolic reading greater than the cutoff value on one or more occasions.

Among patients with severe hypertension in the AVASTIN arms, slightly over half the patients (51%) had a diastolic reading greater than 110 mmHg associated with a systolic reading less than 200 mmHg.

Similar results were seen in patients receiving AVASTIN alone or in combination with FOLFOX4 or carboplatin and paclitaxel. (See WARNINGS: Hypertension and DOSAGE AND ADMINISTRATION: Dose Modifications.)

Neutropenia and Infection

An increased incidence of neutropenia has been reported in patients receiving AVASTIN and chemotherapy compared to chemotherapy alone. In Study 1, the incidence of NCI‑CTC Grade 3 or 4 neutropenia was increased in patients with mCRC receiving IFL+AVASTIN (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of NCI‑CTC Grade 4 neutropenia was increased in patients with NSCLC receiving PC plus AVASTIN (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus AVASTIN vs. 1.8% for PC alone). There were 19 (4.5%) infections with NCI‑CTC Grade 3 or 4 neutropenia in the PC plus AVASTIN arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus AVASTIN arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

Proteinuria

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving AVASTIN has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with AVASTIN, primarily in combination with chemotherapy. High titer human anti‑AVASTIN antibodies were not detected.

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to AVASTIN with the incidence of antibodies to other products may be misleading.

Metastatic Carcinoma of the Colon and Rectum

The data in Tables 4 and 5 were obtained in Study 1. All NCI‑CTC Grade 3 and 4 adverse events and selected NCI‑CTC Grade 1 and 2 adverse events (hypertension, proteinuria, thromboembolic events) were reported for the overall study population. The median age was 60, 60% were male, 79% were Caucasian, 78% had a colon primary lesion, 56% had extra‑abdominal disease, 29% had prior adjuvant or neoadjuvant chemotherapy, and 57% had ECOG performance status of 0. The median duration of exposure to AVASTIN was 8 months in Arm 2 and 7 months in Arm 3. Severe and life threatening (NCI‑CTC Grade 3 and 4) adverse events, which occurred at a higher incidence (≥2%) in patients receiving bolus‑IFL plus AVASTIN as compared to bolus‑IFL plus placebo, are presented in Table 4.

The data in Table 6 were obtained in Study 3. Only NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were reported. The median age was 61 years, 40% were female, 87% were Caucasian, 99% received prior chemotherapy for metastatic colorectal cancer, 26% had received prior radiation therapy, and the 49% had an ECOG performance status of 0. Selected NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events which occurred at a higher incidence in patients receiving FOLFOX4 plus AVASTIN as compared to those who received FOLFOX4 alone, are presented in Table 6. These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 3.

Non‑Squamous, Non‑Small Cell Lung Cancer

The data in Table 7 were obtained in Study 5. Only NCI‑CTC Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were reported. The median age was 63, 46% were female, no patients had received prior chemotherapy, 76% had Stage IV disease, 12% had Stage IIIB disease with malignant pleural effusion, 11% had recurrent disease, and 40% had an ECOG performance status of 0. The median duration of exposure to AVASTIN was 4.9 months.

NCI‑CTC Category TermEvents were reported and graded according to NCI-CTC, Version 2.0. Per protocol, investigators were required to report NCI-CTC Grade 3–5 non‑hematologic and Grade 4 and 5 hematologic events.

No.(%) of NSCLC Patients

PC (n=441)

PC + AVASTIN (n=427)

Any event

286 (65%)

334 (78%)

Blood/bone marrow

Neutropenia

76 (17%)

113 (27%)

Constitutional Symptoms

Fatigue

57 (13%)

67 (16%)

Cardiovascular (general)

Hypertension

3 (0.7%)

33 (8%)

Vascular

Venous thrombus/embolism

14 (3%)

23 (5%)

Infection/febrile neutropenia

Infection without neutropenia

12 (3%)

30 (7%)

Infection with NCI‑CTC Grade 3 or 4 neutropenia

9 (2%)

19 (4%)

Febrile neutropenia

8 (2%)

23 (5%)

Pulmonary/upper respiratory

Pneumonitis/pulmonary infiltrates

11 (3%)

21 (5%)

Metabolic/laboratory

Hyponatremia

5 (1%)

16 (4%)

Pain

Headache

2 (0.5%)

13 (3%)

Renal/genitourinary

Proteinuria

0 (0%)

13 (3%)

Other Serious Adverse Events

The following additional serious adverse events occurred in at least one subject treated with AVASTIN in clinical studies or post‑marketing experience.